Biography

-SOD/cat mimetics as potential mitigators of radiation injury and combined injury, for example, in a radiological accident or terrorism scenario.

-Broader interest in the role of mitochondrial oxidative injury in neurodegenerative and certain other pathological processes.

Over a number of years, beginning at the small pharmaceutical company Eukarion, we developed and have studied synthetic “mito-protective” superoxide dismutase/catalase (SOD/cat) mimetics as potential therapeutic agents for pathologies in which reactive oxygen species (ROS) and reactive nitrogen species (RNS) are implicated. We have focussed on two classes of compounds: (1) Salen manganese complexes that catalytically scavenge ROS and RNS and protect tissues in many experimental models for injury, disease, and degeneration. Examples of these compounds include the “classic” mimetics EUK-8 and EUK-134, the more lipophilic analog EUK-189, and the more biologically-stable cyclic analog EUK-207. All are active in vivo when administered by injection and infusion and, in some cases, topically. (2) Low molecular weight porphyrin manganese complexes, for example EUK-451, with oral bioavailability and anti-apoptotic activity.

In recent years, we’ve had a particular interest in SOD/cat mimetics as potential mitigators of delayed radiation injury. Our lab has conducted this work as part of two BioShield funded, NIAID administered multi-institution “Centers for Medical Countermeasures Against Radiation (CMCR)”. Our CMCRs have studied novel agents for their ability to mitigate delayed injury to kidney, lung, CNS, GI and skin in scenarios relevant to radiological terrorism. Delayed injury to these organ systems is expected to occur weeks, months or years after radiation exposure in survivors of the initial exposure. Such tissue damage is hypothesized to result from chronic oxidative stress through such mechanisms as “proinflammatory” cascades and/or mitochondrial dysfunction. Mitigating effects of SOD/cat mimetics support this hypothesis, and our ongoing research is aimed at elucidating this further. With Dr. John Moulder’s laboratory (Medical College of WI, MCW), we’ve found that EUK-207, initiated weeks after radiation, mitigates chronic renal injury induced by total body irradiation in rats. (This is of potential relevance not only to addressing consequences of radiological accidents or terrorism but also to long-term kidney damage seen in cancer patients undergoing bone marrow transplantation.) Other collaborating CMCR laboratories observe substantial radiation mitigating effects of EUK-207 in the lung (e.g. Mahmood et al., 2011) and brain. More complex scenarios involve “combined injury”, for example radiation and trauma. With collaborators in the labs of Dr Zela Lazarova (MCW) and Dr. Moulder, we’ve found that systemic EUK-207 given beginning 48 hrs after radiation, improves both skin inflammation and wound healing, including angiogenesis, in a rat combined injury (radiation/wounding) model (Doctrow, Lopez et al., 2012). Such data, along with their preservation of microvasculature in irradiated lung (Gao et al., 2012) and inhibition of radiation induced capillary endothelial cell apoptosis (Vorotnikova et al., 2010) suggest that SOD/cat mimetics mitigate injury, at least in part, at the level of the microvascular endothelial cell.

More broadly, we have had a longstanding interest in the role of oxidative stress in neurodegenerative and other disease models, based on the effectiveness, including “structure-activity relationships”, of SOD/cat mimetics. One key target for these compounds is the mitochondrion, an organelle whose dysfunction is strongly implicated in certain neurodegenerative and other chronic disorders. Mice lacking the mitochondrial form of SOD (sod2-/- mice) suffer severe, lethal pathologies due to mitochondrial oxidative injury. With Dr. Simon Melov’s laboratory (Buck Institute), we’ve found that salen Mn complexes, especially the more lipophilic EUK-189, protect the brain and peripheral organs, extending lifespan about 3-fold (Melov et al., 2001; Doctrow et al., 2005). Of all agents, synthetic and natural products, that have been tested so far, EUK-189 continues to be the most “mito-protective” agent in this model, with EUK-207 showing similar activity (Doctrow, Liesa et al., 2012). Studies by Drs. Marc Liesa and Ivan Luptak and colleagues in the labs of Drs Orian Shirihai and Bill Colucci at BUMC have shown that EUK-207 prevents mitochondrial injury in a model for heart ischemia/reperfusion, including in a mouse strain (ABCme -/+) with a mitochondrial impairment (Liesa et al, 2011). (This research was a collaboration through the Mitochondria ARC in the Evans Center for Interdisciplinary Biomedical Research.) Salen Mn complexes also prevent delayed radiation-induced mitochondrial injury, for example in rat astrocytes (Rosenthal et al., 2011). Besides “mito-protection” another likely site of intervention of these SOD/cat mimetics is through suppression of ROS-associated “proinflammatory” transcriptional pathways. For example, they suppress activation of NF kappa B and AP-1 while protecting tissues such as the brain and liver in certain in vivo injury models. Such effects have implications not only in disease and injury, but also in age-associated degeneration. Several years ago, work with Dr. Gordon Lithgow’s lab (Buck Institute) showed that EUK-8 and EUK-134 increased lifespan of c elegans, wild type as well as a strain with a mitochondrial dysfunction (mev-1) (Melov et al., 2000). Other studies with Dr. Michel Baudry’s lab (USC) showed that in aged mice, chronically infused EUK-189 or EUK-207 improved cognitive function in behavioral models, while suppressing numerous biochemical indicators of oxidative stress in the brain (Liu et al., 2003; Clausen et al., 2010). We continue to explore, with our key collaborators, how modulation of mitochondrial function and certain ROS- and RNS-dependent signaling pathways can mediate the effects of SOD/cat mimetics in complex models for injury, aging, and disease. With Pulmonary Center colleagues, we have begun to study asthma, a very complex disorder in which both chronic inflammation and mitochondrial dysfunction have been implicated. In collaboration with Drs. Bill Cruikshank and Marty Joyce-Brady, we are studying the impact of synthetic mito-protective SOD/catalase mimetics, alone or in combination with anti-inflammatory or other experimental therapeutic strategies, in asthma models.